Particle formation

ABSTRACT

Method for preparing a target substance in particulate form, comprising introducing into a particle formation vessel, through separate first and second fluid inlets respectively, (a) a “target solution/suspension” of the substance in a fluid vehicle and (b) a compressed fluid anti-solvent, and allowing the anti-solvent to extract the vehicle so as to form particles of the substance, wherein the anti-solvent fluid has a sonic, near-sonic or supersonic velocity as it enters the vessel, and wherein the anti-solvent and the target solution/suspension enter the vessel at different locations and meet downstream (in the direction of anti-solvent flow) of the second fluid inlet. Also provided is apparatus for use in such a method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 10/197,689, filed Jul. 17, 2002, which is herein incorporatedby reference in its entirety.

FIELD OF THE INVENTION

This invention relates to methods and apparatus for forming particles ofa target substance.

BACKGROUND TO THE INVENTIOn

It is known to use a compressed fluid, typically a supercritical ornear-critical fluid, as an anti-solvent to precipitate particles of asubstance of interest (a “target substance”) from solution orsuspension. The basic technique is known as “GAS” (Gas Anti-Solvent)precipitation [Gallagher et al, “Supercritical Fluid Science andTechnology”, ACS Symp. Ser., 406, p334 (1989)]. Versions of it have beendisclosed for instance in EP-0 322 687 and WO-90/03782, which are herebyincorporated in their entirety by reference.

In one particular version known as SEDS™ (Solution Enhanced Dispersionby Supercritical fluids), a target substance is dissolved or suspendedin an appropriate fluid vehicle, and the resulting “targetsolution/suspension” then co-introduced into a particle formation vesselwith an anti-solvent fluid (usually supercritical) in which the vehicleis soluble. The co-introduction is effected in a particular way, suchthat:

-   -   the target solution/suspension and the anti-solvent both meet        and enter the vessel at substantially the same point; and    -   at that point, the mechanical energy of the anti-solvent serves        to disperse the target solution/suspension (ie, to break it up        into individual fluid elements) at the same time as the        anti-solvent extracts the vehicle so as to cause particle        formation.

Thus, in SEDS™, the compressed fluid serves not only as an anti-solventbut also as a mechanical dispersing agent. The simultaneity of fluidcontact, dispersion and particle formation provides a high degree ofcontrol over the physicochemical properties of the particulate product.

Versions of SEDS™ are described in WO-95/01221, WO-96/00610,WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821, WO-01/15664 andWO-02/38127. Other SEDS™ processes are described in WO-99/52507,WO-99/52550, WO-00/30612, WO-00/30613 and WO-00/67892, all of which arehereby incorporated in their entirety by reference

Another version of the GAS technique is described in WO-97/31691, inwhich a special form of two-fluid nozzle is used to introduce a “targetsolution/suspension” and an energising gas into a particle formationvessel containing a supercritical anti-solvent. The energising gas canbe the same as the anti-solvent fluid. Within the nozzle, a restrictiongenerates sonic waves in the energising gas/anti-solvent flow andfocusses them back (ie, in a direction opposite to that of theenergising gas flow) on the outlet of the target solution/suspensionpassage, resulting in mixing of the fluids within the nozzle before theyenter the particle formation vessel. It is suggested that where theenergising gas is the same as the anti-solvent (typically supercriticalcarbon dioxide), its flow rate could be sufficiently high to obtain asonic velocity at the nozzle outlet. However, the authors do not appearever to have achieved such high velocities in their experimentalexamples.

Other modifications have been made to the basic GAS process in order toaffect atomisation of the target solution/suspension at the point of itscontact with the compressed fluid anti-solvent. For example, U.S. Pat.No. 5,770,559 describes a GAS precipitation process in which a targetsolution is introduced, using a sonicated spray nozzle, into a pressurevessel containing a supercritical or near-critical anti-solventfluid—see also Randolph et al in Biotechnol. Prog., 1993, 9, 429-435.

It would be generally desirable to provide alternative particleformation techniques which combined one or more of the advantages of theprior art methods with a broader applicability (for instance, for awider range of target substances, vehicles and/or anti-solvents) and/ora higher degree of control over the product characteristics. Inparticular it is generally desirable, especially for pharmaceuticalsubstances, to be able to produce small (even sub-micron) particles withnarrow size distributions.

STATEMENTS OF THE INVENTION

According to a first aspect of the present invention there is provided amethod for preparing a target substance in particulate form, the methodcomprising introducing into a particle formation vessel, throughseparate first and second fluid inlet means respectively, (a) a solutionor suspension of the target substance in a fluid vehicle (the “targetsolution/suspension”) and (b) a compressed fluid anti-solvent for thesubstance, and allowing the anti-solvent fluid to extract the vehiclefrom the target solution/suspension so as to form particles of thetarget substance, wherein the anti-solvent fluid has a sonic, near-sonicor supersonic velocity as it enters the particle formation vessel, andwherein the anti-solvent and the target solution/suspension enter theparticle formation vessel at different locations and meet downstream (inthe direction of anti-solvent flow) of the second fluid inlet means.

By “sonic velocity-” and “supersonic velocity” is meant respectivelythat the velocity of the anti-solvent fluid as it enters the vessel isthe same as or greater than the velocity of sound in that fluid at thatpoint. By “near-sonic velocity” is meant that the anti-solvent velocityon entry into the vessel is slightly lower than, but close to, thevelocity of sound in that fluid at that point—for instance its “Machnumber” M (the ratio of its actual speed to the speed of sound) isgreater than 0.8, preferably greater than 0.9 or 0.95. Generallyspeaking, in the method of the invention, the Mach number for theanti-solvent fluid on entering the particle formation vessel may bebetween 0.8 and 1.5, preferably between 0.9 and 1.3.

A near-sonic, sonic or supersonic anti-solvent velocity may be achievedby selecting appropriate operating conditions, in particular thetemperature and pressure of the fluid as it enters the particleformation vessel, the temperature and pressure within the vessel (whichmay be controlled in conventional manner, for instance using an oven anda back pressure regulator) and the geometry (in particular size) of theinlet through which the anti-solvent is introduced into the vessel.

References in this specification to a fluid entering a vessel are to thefluid exiting an inlet means (for example, a nozzle) used to introducethe fluid into the vessel. For these purposes, therefore, the inletmeans is to be considered as upstream of the vessel in the direction offluid flow, although parts of it (in particular its outlet) may belocated physically within the vessel.

There needs to be a drop in pressure as the anti-solvent fluid entersthe particle formation vessel. This is typically achieved by imparting arelatively high “back pressure” to the anti-solvent (by using a highanti-solvent flow rate and forcing it through a restriction such as anozzle) and maintaining the vessel at a significantly lower pressure.

However, this pressure reduction can cause undesirable Joule-Thomsoncooling of the anti-solvent. Accordingly, the temperature of theanti-solvent upstream of the particle formation vessel needs to besufficiently high that the fluid remains at an appropriate temperature(typically above its critical temperature T_(c)), even after expandinginto the particle formation vessel. The method of the invention thuspreferably includes pre-heating the anti-solvent fluid, upstream of theparticle formation vessel, to a temperature such as to compensate forits Joule-Thomson cooling as it enters the vessel.

Thus, the first aspect of the present invention may be seen as a methodfor preparing a target substance in particulate form, the methodcomprising introducing into a particle formation vessel (a) a solutionor suspension of the target substance in a fluid vehicle (the “targetsolution/suspension”) and (b) a compressed fluid anti-solvent for thesubstance, and allowing the anti-solvent fluid to extract the vehiclefrom the target solution/suspension so as to form particles of thetarget substance, wherein (i) the pressure in the particle formationvessel is P₁ which is preferably greater than the critical pressureP_(c) of the anti-solvent, (ii) the anti-solvent is introduced through arestricted inlet so as to have a back pressure of P₂, where P₂ isgreater than P₁, (iii) the temperature in the particle formation vesselis T₁ which is preferably greater than the critical temperature T_(c) ofthe anti-solvent, (iv) the anti-solvent is introduced into the vessel ata temperature T₂, where T₂ is greater than T₁, (v) T₁ and T₂ are suchthat Joule-Thomson cooling of the anti-solvent as it enters the vesseldoes not reduce the anti-solvent temperature to below that required ofit at the point of particle formation (and are preferably such that theanti-solvent temperature does not fall below T_(c) within the vessel)and (vi) P₁, P₂, T₁ and T₂ are such that the anti-solvent fluid has asonic, near-sonic or supersonic velocity as it enters the particleformation vessel.

Again the anti-solvent and the target solution/suspension must beintroduced separately into the particle formation vessel and contacteach other downstream of (preferably immediately downstream of) thepoint of anti-solvent entry into the vessel.

The anti-solvent expansion as it enters the particle formation vessel isisenthalpic. Thus, an appropriate temperature for the anti-solventupstream of the vessel may be derived from enthalpy charts for thefluid, for instance as illustrated for carbon dioxide in FIG. 1. (ForCO₂, the critical temperature T_(c) is 31° C. (304 K) and the criticalpressure P_(c) is 74 bar.) FIG. 1 shows how, when working with apressure reduction from 300 to 80 bar for the CO₂ on entering theparticle formation vessel, the upstream temperature should be at least360 K (87° C.) to achieve an appropriate temperature of 308 K (35° C.)or greater when the CO₂ enters the vessel.

Thus, a carbon dioxide anti-solvent is preferably introduced with anupstream temperature of 80° C. (353 K) or higher, more preferablybetween 80° C. and 170° C. (443 K).

The pressures and temperatures needed to ensure a near-sonic, sonic orsupersonic velocity depend on the nature of the anti-solvent fluid. Inthe case of a carbon dioxide anti-solvent, for instance, in order toachieve a sonic or supersonic velocity the operating conditions mustsatisfy the formula:$\frac{p_{o}}{p_{i}} \leq \left\lbrack \frac{2}{k + 1} \right\rbrack^{\frac{k}{k - 1}}$where p_(i) is the CO₂ pressure upstream of entry into the particleformation vessel and p_(o) is the CO₂ pressure immediately on entry intothe vessel, and k is the ratio of the specific heats of CO₂ at constantpressure (C_(p)) and constant volume (C_(v)).

So, for example the CO₂ may be introduced at a temperature of 360 K (87°C.) with an inlet pressure p_(i) of 300 bar, and the vessel may be at310 K (37° C.) and 80 bar (ie, the outlet pressure p_(o) is 80 bar). At310 K and 80 bar, k for CO₂ is 8.78¹. At 360 K and 300 bar, k is 2.29¹.Taking a geometric average for k of 4.48, as the CO₂ exits the nozzle,then substituting these values into the above equation gives$\frac{p_{o}}{p_{i}} = 0.267$${{and}\left\lbrack \frac{2}{k + 1} \right\rbrack}^{\frac{k}{k - 1}} = 0.274$which confirms that the CO₂ flow is supersonic irrespective of the CO₂flow rate into the vessel, so long as there is an appropriate pressuredifferential between p_(i) and p_(o). A suitable CO₂ flow might be forinstance between 170 and 200 g/min. A suitable pressure drop as the CO₂enters the particle formation vessel might be between 170 and 250 bar.¹International thermodynamic tables of the fluid state −3. Carbondioxide, Angus et al, Pergamon Press, 1976

An alternative method for calculating the anti-solvent velocity (againfor carbon dioxide, using the same operating conditions as above butwith a vessel temperature of 40° C., and introducing the CO₂ through anozzle of outlet diameter 0.2 mm) is:

(i) density of CO₂ at 310 K and 80 bar¹ is 0.33088 g/cm³,

(ii) therefore, volumetric flow of CO₂ at 200 g/min (Q) is200/0.33088=604.45 cm³/min.

(iii) Surface area (A) of the nozzle=3.14×10⁻⁴ cm²,

(iv) therefore velocity of CO₂=Q÷(A×60×100)=320.7 m/s.

(v) Speed of sound in CO₂ at 310 K and 80 bar¹ is 196.8 m/s.

(vi) Thus, the CO₂ velocity is confirmed as being supersonic under suchconditions.

Although we do not wish to be bound by this theory, it is believed thatin the method of the invention, a so-called “Mach disk” is generated inthe anti-solvent flow downstream of the second fluid inlet means. Inthis region the fluid velocity will change abruptly to sub-sonic thusgenerating shock waves in the fluids present (in effect a continuous,low volume, supersonic boom). These shock waves are thought to aidmixing and dispersion of the target solution/suspension with theanti-solvent. It is unlikely that the waves will be ultrasonic as in forexample the system described in WO-97/31691. Moreover they willpropagate in the direction of the anti-solvent flow, rather than in acounter-current sense as in for instance the nozzle described inWO-97/31691 which reflects a sonic wave back towards a source ofenergising gas.

The arrangement of the first and second inlet means will preferably besuch that the Mach disk is generated upstream (in the direction ofanti-solvent flow) of the point of entry of the targetsolution/suspension into the particle formation vessel. It should occurin line with the longitudinal axis of the second inlet means, ie, inline with the direction of anti-solvent flow.

The near-sonic, sonic or supersonic anti-solvent velocity is ideallyachieved, in the method of the present invention, simply by the use ofappropriate anti-solvent flow rates, back pressures and/or operatingtemperatures, and without the aid of mechanical, electrical and/ormagnetic input such as for example from impellers, impinging surfacesespecially within the anti-solvent introducing means, electricaltransducers and the like. Introducing the anti-solvent via a convergentnozzle, ideally as a single fluid stream, may also help in theachievement of appropriate fluid velocities. Further “energising” fluidstreams, such as those required in the method of WO-97/31691, are notthen needed in order to achieve the desired level of control over thecontact between the target solution/suspension and the anti-solventfluid.

The use of near-sonic, sonic or supersonic anti-solvent velocities canallow achievement of smaller particle sizes and narrower sizedistributions in GAS-based particle formation processes. In particularit can allow the formation of small micro- or even nano-particles, forinstance of volume mean diameter less than 5 μm, preferably less than 2μm, more preferably less than 1 μm. Such particulate products preferablyhave narrow size distributions, such as with a standard deviation of 2.5or less, more preferably 2.0 or less, most preferably 1.9 or even 1.8 orless.

The use of near-sonic, sonic or supersonic anti-solvent velocities alsoappears to lead to more efficient vehicle extraction, thus potentiallyyielding particles with lower residual solvent levels, lessagglomeration and generally improved handling properties.

The anti-solvent fluid must be in a compressed state, by which is meantthat it is above its vapour pressure, preferably above atmosphericpressure, more preferably from 70 to 200 bar or from 80 to 150 bar. Morepreferably “compressed” means above the critical pressure P_(c) for thefluid or fluid mixture concerned. In practice, the pressure of theanti-solvent fluid is likely to be in the range (1.01-9.0)P_(c),preferably (1.01-7.0)P_(c).

Thus, the anti-solvent is preferably a supercritical or near-criticalfluid, although it may alternatively be a compressed liquid such as forinstance liquid CO₂.

As used herein, the term “supercritical fluid” means a fluid at or aboveits critical pressure (P_(c)) and critical temperature (T_(c))simultaneously. In practice, the pressure of the fluid is likely to bein the range (1.01-9.0)P_(c), preferably (1.01-7.0)P_(c), and itstemperature in the range (1.01-4.0)T_(c) (measured in Kelvin). However,some fluids (eg, helium and neon) have particularly low criticalpressures and temperatures, and may need to be used under operatingconditions well in excess of (such as up to 200 times) those criticalvalues.

“Near-critical fluid” is here used to refer to a fluid which is either(a) above its T_(c) but slightly below its P_(c), (b) above its P_(c)but slightly below its T_(c) or (c) slightly below both its T_(c) andits P_(c). The term “near-critical fluid” thus encompasses both highpressure liquids, which are fluids at or above their critical pressurebut below (although preferably close to) their critical temperature, anddense vapours, which are fluids at or above their critical temperaturebut below (although preferably close to) their critical pressure.

By way of example, a high pressure liquid might have a pressure betweenabout 1.01 and 9 times its P_(c), and a temperature between about 0.5and 0.99 times its T_(c). A dense vapour might, correspondingly, have apressure between about 0.5 and 0.99 times its P_(c), and a temperaturebetween about 1.01 and 4 times its T_(c).

The terms “supercritical fluid” and “near-critical fluid” each encompassa mixture of fluid types, so long as the mixture is in the supercriticalor near-critical state respectively.

In the method of the present invention, it may be preferred that theoperating temperature (ie, the temperature in the particle formationvessel) be close to the critical temperature T_(c) of the mixture ofanti-solvent and target solution/suspension formed at the point of fluidcontact. For example, the temperature might be between 0.9 and 1.1 timesT_(c) (in Kelvin), preferably between 0.95 and 1.05 times T_(c), morepreferably between 0.97 and 1.03 or between 0.98 and 1.02 times T_(c),or perhaps between 1 and 1.05 or 1 and 1.03 or 1 and 1.02 times T_(c).This is because at T_(c) the velocity of sound in a fluid istheoretically zero; near-sonic, sonic and supersonic velocities can thusmore readily be achieved, using lower anti-solvent flow rates, as T_(c)is approached.

The anti-solvent should be a compressed (preferably supercritical ornear-critical, more preferably supercritical) fluid at its point ofentry into the particle formation vessel and preferably also within thevessel and throughout the particle formation process. Thus, for a carbondioxide anti-solvent the temperature in the particle formation vessel isideally greater than 31° C., for example between 31 and 100° C.,preferably between 31 and 70° C., and the pressure greater than 74 bar,for example between 75 and 350 bar.

Carbon dioxide is a highly suitable anti-solvent, but others includenitrogen, nitrous oxide, sulphur hexafluoride, xenon, ethylene,chlorotrifluoromethane, ethane, trifluoromethane and noble gases such ashelium or neon.

The anti-solvent must be miscible or substantially miscible with thefluid vehicle at the point of their contact, so that the anti-solventcan extract the vehicle from the target solution/suspension. By“miscible” is meant that the two fluids are miscible in all proportions,and “substantially miscible” encompasses the situation where the fluidscan mix sufficiently well, under the operating conditions used, as toachieve the same or a similar effect, ie, dissolution of the fluids inone another and precipitation of the target substance. However theanti-solvent must not, at the point of particle formation, extract ordissolve the target substance. In other words, it must be chosen so thatthe target substance is for all practical purposes (in particular, underthe chosen operating conditions and taking into account any fluidmodifiers present) insoluble or substantially insoluble in it.Preferably the target substance is less than 10-3 mole %, morepreferably less than 10-5 mole %, soluble in the anti-solvent fluid.

The anti-solvent fluid may optionally contain one or more modifiers, forexample water, methanol, ethanol, isopropanol or acetone. A modifier (orco-solvent) may be described as a chemical which, when added to a fluidsuch as a supercritical or near-critical fluid, changes the intrinsicproperties of that fluid in or around its critical point, in particularits ability to dissolve other materials. When used, a modifierpreferably constitutes not more than 40 mole %, more preferably not morethan 20 mole %, and most preferably between 1 and 10 mole %, of theanti-solvent fluid.

The vehicle is a fluid which is able to carry the target substance insolution or suspension. It may be composed of one or more componentfluids, eg, it may be a mixture of two or more solvents. It must besoluble (or substantially soluble) in the chosen anti-solvent fluid attheir point of contact. It may contain, in solution or suspension, othermaterials apart from the target substance.

The target solution/suspension may in particular comprise two or morefluids which are mixed in situ at or immediately before their contactwith the anti-solvent. Such systems are described, eg, in WO-96/00610and WO-01/03821. The two or more fluids may carry two or more targetsubstances, to be combined in some way (for instance, co-precipitated asa matrix, or one precipitated as a coating around the other, orprecipitated as the product of an in situ reaction between thesubstances) at the point of particle formation. Target substance(s) mayalso be carried in the anti-solvent fluid as well as in the targetsolution(s)/suspension(s).

The target substance may be any substance which needs to be produced inparticulate form. Examples include pharmaceuticals; pharmaceuticalexcipients such as carriers; dyestuffs; cosmetics; foodstuffs; coatings;agrochemicals; products of use in the ceramics, explosives orphotographic industries; etc . . . It may be organic or inorganic,monomeric or polymeric. It is preferably soluble or substantiallysoluble in the fluid vehicle, preferably having a solubility in it of10-4 mole % or greater under the conditions under which the targetsolution is prepared (ie, upstream of the point of particle formation).

In a preferred embodiment of the invention, the target substance is foruse in or as a pharmaceutical or pharmaceutical excipient.

The target substance may be in a single or multi-component form (eg, itcould comprise an intimate mixture of two materials, or one material ina matrix of another, or one material coated onto a substrate of another,or other similar mixtures). The particulate product, formed from thetarget substance using the method of the invention, may also be in sucha multi-component form—examples include two pharmaceuticals intended forco-administration, or a pharmaceutical together with a polymer carriermatrix. Such products may be made (as described above) fromsolutions/suspensions containing only single component startingmaterials, provided the solutions/suspensions are contacted with theanti-solvent fluid in the correct manner. The particulate product maycomprise a substance formed from an in situ reaction (ie, immediatelyprior to, or on, contact with the anti-solvent) between two or morereactant substances each carried by an appropriate vehicle.

In the method of the invention, the anti-solvent and the targetsolution/suspension are introduced separately into the particleformation vessel (which is preferably the vessel in which the formedparticles are collected) and contact each other after (preferablyimmediately after) their point of entry into the vessel. In this way,particle formation can be made to occur at a point where there is a highdegree of control over conditions such as the temperatures, pressuresand flow rates of the fluids.

The fluids are ideally introduced in such a way that the mechanical(kinetic) energy of the anti-solvent fluid can act to disperse thetarget solution/suspension at the same time as it extracts the vehicle;this again allows a high degree of control over the physicochemicalcharacteristics of the particulate product, in particular the size andsize distribution of the particles and their solid state properties.“Disperse” in this context refers generally to the transfer of kineticenergy from one fluid to another, usually implying the formation ofdroplets, or of other analogous fluid elements, of the fluid to whichthe kinetic energy is transferred. Thus, the fluid inlet means used tointroduce the fluids should allow the mechanical energy (typically theshearing action) of the anti-solvent flow to facilitate intimate mixingof the fluids and to disperse them, at the point where the fluids meet.

Introducing the two fluids separately in this way can help preventapparatus blockages at the point of anti-solvent entry, due for exampleto the highly efficient extraction of the vehicle into the anti-solventunder the operating conditions used.

Thus, the present invention may be seen as a modification of the SEDS™process, in which the target solution/suspension and the anti-solventfluid contact one another externally of their respective (preferablyseparate) fluid inlets into the particle formation vessel. A high degreeof control is retained over the mechanism for fluid contact, as in thebasic SEDS™ process, and this control may be achieved for example atleast partly by introducing the anti-solvent fluid with a sonic,near-sonic or supersonic velocity. Other ways in which such control maybe achieved or improved upon include providing controlled agitationwithin the particle formation vessel, in particular in the region offluid contact immediately downstream of the respective targetsolution/suspension and anti-solvent inlets. For example, the targetsolution/suspension may be dispersed onto a sonicating surface at orimmediately prior to its contact with the anti-solvent fluid. Agitationmay alternatively be achieved for instance by stirring, such as with aturbine, propeller, paddle, impeller or the like.

That said, the present invention may if necessary be practised in theabsence of such additional agitation means within the particle formationvessel.

The target solution/suspension may be introduced into the vessel throughany suitable fluid inlet means, including one which effects, or assistsin effecting, controlled atomisation of the solution/suspension.

Preferably the two fluids meet immediately downstream of the point ofanti-solvent entry. “Immediately” in this context implies a sufficientlysmall time interval (between the anti-solvent entering the particleformation vessel and its contact with the target solution/suspension) aspreferably still to allow transfer of mechanical energy from theanti-solvent to the solution/suspension so as to achieve dispersion.Nevertheless, there is still preferably a short interval of time betweenanti-solvent entry and fluid contact so as to eliminate, orsubstantially eliminate or at least reduce, the risk of apparatusblockage due to particle formation at the point of anti-solvent entry.The timing of the fluid contact will depend on the natures of thefluids, the target substance and the desired end product, as well as onthe size and geometry of the particle formation vessel and the apparatusused to introduce the fluids and on the fluid flow rates. The contactmay occur within 0.5 to 10 seconds, more preferably within 1 to 7seconds, most preferably within 1.2 to 6 seconds, such as within 1.4 to5.5 seconds, of the anti-solvent entering the particle formation vessel.

The target solution/suspension is preferably introduced directly intothe anti-solvent flow. It preferably meets with the anti-solvent flow atthe point where the target solution/suspension enters the vessel.

Preferably the outlet of the first fluid inlet means is locatedvertically below that of the second fluid inlet means, and theanti-solvent fluid flows into the particle formation vessel in avertically downwards direction.

At the point where the target solution/suspension and the anti-solventmeet, the angle between their axes of flow may be from 0° (ie, the twofluids are flowing in parallel directions) to 180° (ie,oppositely-directed flows). However, they preferably meet at a pointwhere they are flowing in approximately perpendicular directions, ie,the angle between their axes of flow is from 70 to 110°, more preferablyfrom 80 to 100°, such as 90°.

Suitable fluid inlet means, which may be used to achieve the form offluid contact required by the first aspect of the invention, isdescribed below in connection with the second aspect.

Use of such a fluid inlet system can allow SEDS™ and other GAS-basedparticle formation techniques to be practised in cases where the vehiclefor the target solution/suspension is a relatively high boiling fluid(eg, boiling point greater than about 150° C., or even greater than 180°C.) such as dimethyl formamide (DMF), dimethyl sulphoxide (DMSO),dimethyl acetamide (DMA), diethyl acetamide (DEA) or N-methylpyrollidinone (NMP), or where the target substance is temperaturesensitive. Since the anti-solvent and the target solution/suspensionenter the vessel separately, the latter can be maintained at a desiredlower temperature despite the use of a relatively high temperature forthe incoming anti-solvent. Moreover, the use of a sonic, near-sonic orsupersonic anti-solvent velocity can be sufficient to disperse thetarget solution/suspension at relatively low operating temperatures (ie,vessel temperatures)—again this assists in the processing of temperaturesensitive target substances and vehicles.

When carrying out the present invention, the particle formation vesseltemperature and pressure are ideally controlled so as to allow particleformation to occur at or substantially at the point where the targetsolution/suspension meets the anti-solvent fluid. The conditions in thevessel must generally be such that the anti-solvent fluid, and thesolution which is formed when it extracts the vehicle, both remain inthe compressed (preferably supercritical or near-critical, morepreferably supercritical) form whilst in the vessel. For thesupercritical, near-critical or compressed solution, this means that atleast one of its constituent fluids (usually the anti-solvent fluid,which in general will be the major constituent of the mixture) should bein a compressed state at the time of particle formation. There should atthat time be a single-phase mixture of the vehicle and the anti-solventfluid, otherwise the particulate product might be distributed betweentwo or more fluid phases, in some of which it might be able toredissolve. This is why the anti-solvent fluid needs to be miscible orsubstantially miscible with the vehicle.

The terms “supercritical solution”, “near-critical solution” and“compressed solution” mean respectively a supercritical, near-criticalor compressed fluid together with a fluid vehicle which it has extractedand dissolved. The solution should itself still be in the supercritical,near-critical or compressed state, as the case may be, and exist as asingle phase, at least within the particle formation vessel.

Selection of appropriate operating conditions will be influenced by thenatures of the fluids involved (in particular, their P_(c) and T_(c)values and their solubility and miscibility characteristics) and also bythe characteristics desired of the particulate end product, for instanceyield, particle size and size distribution, purity, morphology, orcrystalline, polymorphic or isomeric form. Variables include the flowrates of the anti-solvent fluid and the target solution/suspension, theconcentration of the target substance in the vehicle, the temperatureand pressure inside the particle formation vessel, the anti-solventtemperature upstream of the vessel and the geometry of the fluid inletsinto the vessel, in particular the size of the anti-solvent inlet. Themethod of the invention preferably involves controlling one or more ofthese variables so as to influence the physicochemical characteristicsof the particles formed.

The flow rate of the anti-solvent fluid relative to that of the targetsolution/suspension, and its pressure and temperature, should besufficient to allow it to accommodate the vehicle, so that it canextract the vehicle and hence cause particle formation. The anti-solventflow rate will generally be higher than that of the targetsolution/suspension—typically, the ratio of the targetsolution/suspension flow rate to the anti-solvent flow rate (bothmeasured at or immediately prior to the two fluids coming into contactwith one another) will be 0.001 or greater, preferably from 0.01 to 0.2,more preferably from about 0.03 to 0.1.

The anti-solvent flow rate will also generally be chosen to ensure anexcess of the anti-solvent over the vehicle when the fluids come intocontact, to minimise the risk of the vehicle re-dissolving and/oragglomerating the particles formed. At the point of extraction of thevehicle it may constitute from 1 to 80 mole %, preferably 50 mole % orless or 30 mole % or less, more preferably from 1 to 20 mole % and mostpreferably from 1 to 5 mole %, of the compressed fluid mixture formed.

Both the anti-solvent and the target solution/suspension are ideallyintroduced into the particle formation vessel with a smooth, continuousand preferably pulse-less or substantially pulse-less flow. Conventionalapparatus may be used to ensure such fluid flows.

The method of the invention preferably additionally involves collectingthe particles following their formation, more preferably in the particleformation vessel itself.

According to a second aspect of the present invention, there is providedapparatus for use in preparing a target substance in particulate form,and in particular for use in a method according to the first aspect ofthe invention, the apparatus comprising:

(i) a particle formation vessel;

(ii) first fluid inlet means for introducing into the vessel a solutionor suspension of the target substance in a fluid vehicle (the “targetsolution/suspension”); and

(iii) second fluid inlet means, separate from the first, for introducinga compressed fluid anti-solvent into the particle formation vessel;

wherein the first and second fluid inlet means are so arranged that, inuse, a target solution/suspension introduced through the first and ananti-solvent introduced through the second enter the particle formationvessel at different locations and meet immediately downstream (in thedirection of anti-solvent flow) of the second fluid inlet means.

The first fluid inlet means suitably comprises a fluid inlet tube, forinstance of stainless steel, which might typically have an internaldiameter of from 0.1 to 0.2 mm, more preferably from 0.1 to 0.15 mm, andmay have a tapered outlet section.

The second fluid inlet means preferably provides a restriction at thepoint of fluid entry into the particle formation vessel: for instance,the second fluid inlet means may comprise a nozzle. Again it maysuitably be made from stainless steel. It preferably has at least onepassage of internal diameter from for instance 1 to 2 mm, morepreferably from 1.3 to 1.9 mm, such as 1.6 mm. Again, it may have atapered outlet section (ie, be a “convergent”-type nozzle), with anangle of taper (with respect to the longitudinal axis of the nozzle)typically in the range 10° to 60°, preferably from 10° to 50°, morepreferably from 20° to 40°, and most preferably about 30°.

The opening at the outlet end (tip) of the nozzle will preferably have adiameter in the range of 0.005 to 5 mm, more preferably 0.05 to 2 mm,most preferably from 0.1 to 0.5 mm, for instance about 0.1, 0.2, 0.3 or0.35 mm.

The dimensions of the fluid inlet will naturally depend on the scale onwhich the process is to be practised; for commercial scale manufacture,for example, the above nozzle dimensions may be up to ten times larger.

A nozzle of the above type may comprise more than one fluid passage; forinstance it may comprise two or more coaxial passages such as in thenozzles described in WO-95/01221, WO-96/00610 and WO-98/36825,particularly if additional fluids are to be introduced into the system.One or more of the passages may be used to introduce two or more fluidsat the same time, and the inlets to such passages may be modifiedaccordingly.

The outlet of the first fluid inlet means (into the particle formationvessel) is preferably immediately downstream, in the direction ofanti-solvent flow in use, of that of the second fluid inlet means. Asuitable separation for the two outlets is a short distance such as from0 to 50, preferably from 10 to 40, for instance about 20 times thediameter of the outlet of the second fluid inlet means. Suitabledistances might lie from 0 to 10 mm or from 0.1 to 10 mm, preferablyfrom 2 to 8 mm, for instance about 4 mm. Again, they may depend on thescale of the process which the inlet means are to be used for.

The outlet of the first fluid inlet means preferably has a smaller crosssectional area than that of the second fluid inlet means, morepreferably less than 80% as large and most preferably less than 70% or65% as large. Preferably this outlet is positioned such that, in use, itis within the flow of anti-solvent fluid exiting the second fluid inletmeans. Most preferred is an arrangement in which the centre of theoutlet of the first fluid inlet means corresponds to the centre of theoutlet of the second fluid inlet means, ie, the centres of the twooutlets are both positioned on the central longitudinal axis of thesecond fluid inlet means.

The first and second fluid inlet means are preferably arranged so thatat the point where the target solution/suspension and the anti-solventmeet, the angle between their axes of flow is from 70° to 110°, morepreferably from 80 to 100°, most preferably about 90°.

The first and second fluid inlet means may for convenience be providedas part of a single fluid inlet assembly which may be placed in fluidcommunication with the particle formation vessel and with sources of theanti-solvent fluid and the target solution/suspension.

Thus, according to a third aspect, the present invention provides afluid inlet assembly for use as part of apparatus according to thesecond aspect of the invention, and/or in a method according to thefirst aspect.

In apparatus according to the second aspect of the invention, theparticle formation vessel preferably contains particle collection means,such as a filter, by which particles of the target substance may becollected in the vessel in which they form, downstream of the point ofcontact between the target solution/suspension and the anti-solventfluid.

The apparatus may additionally comprise a source of a compressed(preferably supercritical or near-critical) fluid and/or a source of atarget solution or suspension. The former may itself comprise means foraltering the temperature and/or pressure of a fluid so as to bring itinto a compressed (preferably supercritical or near-critical) state. Theapparatus conveniently includes means for controlling the pressure inthe particle formation vessel, for example a back pressure regulatordownstream of the vessel, and/or means (such as an oven) for controllingthe temperature in the vessel. The vessel is conveniently a pressurevessel and should be capable of withstanding the pressures necessary tomaintain compressed (preferably supercritical or near-critical)conditions during the particle formation process, as described above inconnection with the method of the invention.

Because embodiments of the present invention are modified versions ofthe inventions disclosed in WO-95/01221, WO-96/00610, WO-98/36825,WO-99/44733, WO-99/59710, WO-01/03821, WO-01/15664 and WO-02/38127,technical features described in those documents, for instance regardingthe selection of appropriate reagents and operating conditions, canapply also to the present invention. The eight earlier documents aretherefore intended to be read together with the present application.

In this specification the term “substantially”, when applied to acondition, is meant to encompass the exact condition (eg, exactsimultaneity) as well as conditions which are (for practical purposes,taking into account the degree of precision with which such conditionscan be measured and achieved) close to that exact condition, and/orwhich are similar enough to that exact condition as to achieve, incontext, the same or a very similar effect.

References to solubilities and miscibilities, unless otherwise stated,are to the relevant fluid characteristics under the operating conditionsused, ie, under the chosen conditions of temperature and pressure andtaking into account any modifiers present in the fluids.

The present invention will now be illustrated with reference to thefollowing non-limiting examples and the accompanying figures, of which:

FIG. 1 is a plot of the enthalpy variation of CO₂ with temperature andpressure, illustrating the change in CO₂ temperature during itsisenthalpic expansion;

FIG. 2 illustrates schematically apparatus suitable for use in carryingout a method according to the present invention;

FIGS. 3 to 5 are schematic longitudinal cross sections and an under planview respectively of parts of a fluid inlet assembly useable with theFIG. 2 apparatus;

FIGS. 6 to 9 are SEM (scanning electron microscope) photographs of theproducts of Examples A1, A2, A5 and A6 (below) respectively;

FIGS. 10 and 10B show particle size distributions for the product ofExample B1;

FIGS. 11A and 11B show particle size distributions for the product ofExample B2;

FIGS. 12A and 12B show particle size distributions for the product ofExample B3;

FIGS. 13 and 14 are SEM photographs of the products of Examples D1 andD2 respectively;

FIGS. 15A and 15B show particle size distributions for the product ofExample D1;

FIGS. 16A and 16B show particle size distributions for the product ofExample D2; and

FIGS. 17 and 18 are SEM photographs of the products of Examples E2 andE3 respectively.

DETAILED DESCRIPTION

FIG. 2 shows apparatus suitable for carrying out methods in accordancewith the present invention. Item 1 is a particle formation vessel,within which the temperature and pressure can be controlled by means ofthe heating jacket 2 and back pressure regulator 3. The vessel 1contains a particle collection device (not shown) such as a filter,filter basket or filter bag. A fluid inlet assembly 4 allowsintroduction of a compressed (typically supercritical or near-critical)fluid anti-solvent from source 5 and one or more targetsolutions/suspensions from sources such as 6 and 7. The items labelled 8are pumps, and 9 is a cooler. A recycling system 11 allows solventrecovery.

The fluid inlet assembly 4 may for example take the form shown in FIGS.3 to 5. FIG. 3 shows the assembly schematically, in use with theparticle formation vessel 1 of the FIG. 2 apparatus. Nozzle 21 is forintroduction of the anti-solvent fluid. It has only a single passage ofcircular cross section, with a circular outlet 22. Alternatively, amulti-component nozzle may be used, with anti-solvent introduced throughone or more of its passages and the remaining passages either closed offor else used to introduce additional reagents. (For example, amulti-passage nozzle of the type described in WO-95/01221 or WO-96/00610may be used. Such nozzles have two or more concentric (coaxial)passages, the outlets of which are typically separated by a shortdistance to allow a small degree of internal mixing to take placebetween fluids introduced through the respective passages before theyexit the nozzle. The anti-solvent could for instance be introducedthrough the inner passage of such a nozzle, traversing a small “mixing”zone as it exits that inner passage and then passing through the mainnozzle outlet into the particle formation vessel.)

Inlet tube 23 is for introduction of the target solution/suspension, andis so shaped and located that the direction of flow of thesolution/suspension at its outlet 24 (see FIG. 5) will be perpendicularto that of the anti-solvent exiting nozzle 21. Again the tube is ofcircular cross section.

FIG. 4 shows how tube 23 is mounted, by means of the supporting andlocking pieces 25, on a collar 26 which is itself mounted around thelower portion of the nozzle 21. The arrangement is such as to allowadjustment of the distance “d” between the outlets of nozzle 21 and tube23. It can be seen that the outlet of tube 23 is positioned on thecentral longitudinal axis of the nozzle 21.

Both the nozzle 21 and the tube 23 are preferably made from stainlesssteel.

The assembly of FIGS. 3 to 5 may be less likely to suffer blockages (atthe nozzle and tube outlets) than a multi-component SEDS™ nozzle of thetype described in WO-95/01221, particularly when the operatingconditions are such as to allow a very rapid and efficient removal ofthe solvent vehicle, from the target solution/suspension, by theanti-solvent.

EXAMPLES

Apparatus as shown in FIG. 2, incorporating a fluid inlet assembly asshown in FIGS. 3 to 5, was used to carry out particle formation methodsin accordance with the invention. The nozzle 21 comprised a fluid inlettube of internal diameter 1.6 mm and an outlet of diameter 0.2 mm. Theinternal bore at the end of the inlet tube 23 was 0.125 mm. The verticalseparation “d” between the nozzle and tube outlets was varied between 0and 8 mm, “0” representing the situation where the solution tube 23contacted the lower end of the nozzle 21.

Supercritical carbon dioxide was used as the anti-solvent. It was pumpedat a flow rate (of liquid CO₂, prior to passing through a heater) of 200g/min. Its temperature on entry into the nozzle 21 was 356 K (83° C.).

The pressure in the particle formation vessel 1 (capacity 2 litres) wasmaintained at 80 bar and 309-313 K (36-40° C.). The CO₂ back pressurewas between 250 and 300 bar. These conditions created a sonic orsupersonic CO₂ velocity at the nozzle outlet 22.

Examples A

Various target compounds were dissolved in appropriate solvents andintroduced into the apparatus via tube 23. The distance “d” between theoutlets of the anti-solvent nozzle and the solution inlet tube was keptconstant at 4 mm. Particle formation was allowed to occur by the actionof the CO₂ anti-solvent, and the products collected in the vessel 1. Theproducts were assessed by scanning electron microscopy (SEM) and in mostcases their particle sizes analysed using an Aerosizer™ and/or Sympatec™system.

The results of these experiments are shown in Table 1 below. TABLE 1Target Target solution solution Product size Product size Targetconcentration flow rate (Aerosizer ™) (Sympatec ™) Expt no. solution (%w/v) (ml/min) (μm) (μm) A1 Compound I 3 4 2.84 — in methanol A2 CompoundII 1.75 4 — 5.75 in methanol A3 Compound 3 0.5 1.39 7.99 III in DMF A4Compound 0.85 4 — — IV in DMF A5 Compound 3 1 — 4.6 V in DMSO A6Compound 5 1 0.97 2.5 VI in THF

SEM photographs of the products of Experiments A1, A2, A5 and A6 areshown in FIGS. 6 to 9 respectively.

Examples B

In these experiments, the distance “d” between the outlets of theanti-solvent nozzle 21 and the solution inlet tube 23 was varied between0 and 8 mm. In practice, the “0” separation represented the thickness ofthe inlet tube wall—in other words, as close to zero as was possiblewithout cutting into the nozzle wall. The target solution was 3% w/vcompound I in methanol; its flow rate into the particle formation vessel1 was 4 ml/min.

The results are shown in Table 2 below. TABLE 2 Distance Product size“d” (Aerosizer ™) Expt no. (mm) (μm) B1 0 3.21 B2 4 2.84 B3 8 3.63

The particle size distributions (by Aerosizer™) for the products ofExamples B1, B2 and B3 are shown in FIGS. 10A and 10B, 11A and 11B, and12A and 12B respectively.

Examples C

These experiments investigated the effect of the target solution flowrate on the product particle size. Again various target compounds weretested, the operating conditions being as for Examples A.

The results are given in Table 3 below. TABLE 3 Target Target solutionsolution Product size Product size Expt concentration flow rate(Aerosizer ™) (Sympatec ™) no. Target solution (% w/v) (ml/min) (μm)(μm) C1 Compound II in 0.75 2 — 7.8 acetone C2 Compound II in 0.75 4 —4.75 acetone C3 Compound IV in 0.85 1 — — DMF C4 Compound IV in 0.85 4 —— DMF C5 Compound IV in 0.85 8 — — DMF C6 Compound III in 3 0.5 1.397.99 DMF C7 Compound III in 3 1.0 1.86 7.18 DMF C8 Compound III in 3 418.18 10.5 DMF C9 Compound V in 1.6 1 — 9.1 DMF(ac)* C10 Compound V in1.6 4 — 42.3 DMF(ac)* C11 Compound VI in 5 1 0.97 2.5 THF C12 CompoundVI in 5 4 1.18 3.0 THF*DMF(ac) = DMF acidified with 4% v/v acetic acid

Examples D

These experiments compared two types of fluid inlet assembly. In ExampleD1, a two-fluid coaxial nozzle of the type described in WO-95/01221 wasused to co-introduce supercritical CO₂ and Compound VI in solution inTHF (tetrahydrofuran). The internal diameter of the inner nozzlepassage, through which the CO₂ was introduced, was 1.6 mm; that of theouter passage, through which the target solution was introduced, 2.5 mm.The nozzle outlet diameter was 0.2 mm.

In Example D2, an assembly of the type illustrated in FIGS. 3 to 5, witha nozzle outlet separation “d” of 4 mm, was used to introduce the samereagents. The CO₂ was introduced through the inner passage of the nozzleused in Example D1; the outer nozzle passage was not used.

All other operating conditions were the same for both experiments.Within the particle formation vessel the temperature was 309 K (36° C.)and the pressure was 80 bar. The target solution concentration was 5%w/v and its flow rate 1 ml/min. The CO₂ flow rate was 200 g/min and itsinlet temperature 356 K (83° C.).

The results are given in Table 4 below. TABLE 4 Product size Expt (SEM)(Aerosizer ™) no. (μm) (μm) D1 1-6 μm 2.54 D2 750 nm-4 μm 1.5

SEMs for the products of Examples D1 and D2 are shown in FIGS. 13 and 14respectively. Their Aerosizer™ particle size distributions are shown inFIGS. 15A and B and 16A and B respectively, D2 showing a significantlysmaller particle size and a better distribution than D1.

It was also found that the fluid inlet assembly of FIGS. 3 to 5 (ExampleD2) gave a less agglomerated product.

Examples E

Two further target compounds, dihydroergotamine mesylate (Compound VII)and ipratropium bromide (Compound VIII) were prepared using a vesseltemperature of 309 K (36° C.) and pressure of 80 bar, a CO₂ flow rate of200 g/min and a nozzle separation “d” of 4 mm. The CO₂ temperatureupstream of the vessel was 356 K (83° C.). Particle sizes were assessedusing the Aerosizer™.

The results are shown in Table 5 below. TABLE 5 Target Target solutionsolution Product size Expt concentration flow rate CO₂ flow rate(Aerosizer ™) no. Target solution (% w/v) (ml/min) (ml/min) (μm) E1Compound VII 4.0 1.0 200 6.78 in methanol E2 Compound VII 2.0 1.0 2100.87 in methanol:water (9:1 v/v) E3 Compound VIII 1.0 2.0 210 3.79 inmethanol:water (95:5 v/v) E4 Compound VIII 1.0 4.0 210 5.62 inmethanol:water (95:5 v/v)

SEM photographs of the products of Experiments E2 and E3 are shown inFIGS. 17 and 18 respectively.

Examples F

Two drugs suitable for delivery by inhalation therapy were producedusing the method of the invention. In all cases the products were fine,free-flowing powders having excellent dispersibility in fluids such asin particular the propellant fluids used to aerosolise such activesubstances in so-called “metered dose inhalers”. The drugs exhibitedimproved flocculation performance in such propellants (in particular inHFA 134a and HFA 227ea), as compared to the performance of micronisedversions of the same drugs having comparable particle sizes.

For these experiments, the CO₂ anti-solvent was pumped at different flowrates, as shown in Table 6 below. Its temperature on entry into thenozzle 21 of the FIG. 2 apparatus was 363 K (90° C.). The pressure inthe particle formation vessel 1 (capacity 2000 ml) was maintained at 80bar and 309 K (36° C.). The vertical separation “d” between the nozzleand solution tube outlets was 4 mm.

The reagents, solvents and other relevant operating conditions aresummarised in Table 6, together with the particle sizes and sizedistributions of the products. TABLE 6 Target Target Product solutionsolution CO₂ flow MMAD Particle Expt Target concn (% flow rate rate D(4, 3) size no. substance Vehicle w/v) (ml/min) (ml/min) (μm) spread F1Salmeterol Methanol 3 4 158 1.7 (A) 1.8 (A) xinafoate F2 Risperidone-THF 5 4 200 3.0 (S) 1.52 (S) (9-hydroxy)- palmitate F3 Risperidone- THF5 1 200 2.5 (S) 1.52 (S) (9-hydroxy)- palmitate

The particle sizes quoted in Table 6 are, where indicated (A), massmedian aerodynamic diameters obtained using an Aerosizer™ time-of-flightinstrument and, where indicated (S), geometric projection equivalentmass median diameters obtained using the Helos™ system available fromSympatec GmbH, Germany.

The particle size spread is defined as (D90−D10)/D50 and indicates hownarrow the size distribution may be for products made according to thepresent invention.

The flocculation behaviour of the products of Examples F, in thepropellants HFA 134a and HFA 227ea, are documented in our co-pending UKpatent application no. 0208742.7.

1. A method for preparing a pharmaceutical substance in particulateform, the method comprising: separately introducing into a particleformation vessel the substance in a fluid vehicle through a first fluidinlet; separately introducing into the particle formation vessel acompressed fluid anti-solvent for the substance through a second fluidinlet; and allowing the compressed fluid anti-solvent to extract thefluid vehicle from the substance to form particles of the substance,wherein the compressed fluid anti-solvent has a sonic, near-sonic orsupersonic velocity as it enters the particle formation vessel, andwherein the compressed fluid anti-solvent and the substance in the fluidvehicle enter the particle formation vessel at different locations andcontact each other after their point of entry.
 2. The method of claim 1,wherein the substance in the fluid vehicle is a solution, a suspensionor a combination thereof.
 3. The method of claim 2, wherein thecompressed fluid anti-solvent is a supercritical or near-critical fluid.4. The method of claim 3, wherein the supercritical fluid ornear-critical fluid contains a compound selected from the groupconsisting of carbon dioxide, nitrogen, nitrous oxide, sulfurhexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane,trifluoromethane, helium, neon, derivatives thereof and combinationsthereof.
 5. The method of claim 1, wherein: the pressure in the particleformation vessel is P₁; and the compressed fluid anti-solvent isintroduced through a restricted inlet so as to have a back pressure ofP₂ as it is introduced into the particle formation vessel, where P₂ isgreater than P₁.
 6. The method of claim 5, wherein: the temperature inthe particle formation vessel is T₁; and the compressed fluidanti-solvent is introduced into the particle formation vessel at atemperature T₂, where T₂ is greater than T₁.
 7. The method of claim 6,wherein T₁ and T₂ are such that Joule-Thomson cooling of the compressedfluid anti-solvent as it enters the particle formation vessel does notreduce the temperature of the compressed fluid anti-solvent to below acritical temperature T_(c) of the anti-solvent.
 8. The method of claim7, wherein P₁, P₂, T₁ and T₂ are such that the compressed fluidanti-solvent has a sonic, near-sonic or supersonic velocity as it entersthe particle formation vessel.
 9. The method of claim 8, wherein: thecompressed fluid anti-solvent is supercritical or near-critical carbondioxide; P₁ is between about 75 bar and about 350 bar; P₂ is betweenabout 250 bar and about 350 bar; T₁ is between about 31° C. and about100° C.; and T₂ is between about 80° C. and about 170° C.,
 10. Themethod of claim 9, wherein the carbon dioxide has a flow rate of betweenabout 170 g/min and about 200 g/min; and P₁ and P₂ have a differencebetween about 170 bar and about 250 bar.
 11. The method of claim 6,wherein: P₁ is greater than a critical pressure P_(c) of theanti-solvent, T₁ is greater than a critical temperature T_(c) of theanti-solvent; and T₁ and T₂ are such that the temperature of thecompressed fluid anti-solvent does not fall below T_(c) within theparticle formation vessel.
 12. The method of claim 2, wherein onentering the particle formation vessel, the compressed fluidanti-solvent has a Mach number between about 0.8 and about 1.5.
 13. Themethod of claim 2, wherein the near-sonic, sonic or supersonic velocityof the compressed fluid anti-solvent is achieved by introducing thecompressed fluid anti-solvent into the particle formation vessel as asingle stream through a convergent nozzle, without the aid of furthermechanical, electrical and/or magnetic input.
 14. The method of claim 2,wherein a Mach disk is generated in the compressed fluid anti-solvent asit enters the particle formation vessel.
 15. The method of claim 14,wherein shock waves from the Mach disk propagate in the direction of thecompressed fluid anti-solvent flow.
 16. The method of claim 2, whereinthe compressed fluid anti-solvent is a supercritical fluid.
 17. Themethod of claim 2, wherein the fluid vehicle comprises two or morefluids which are mixed in situ at or immediately before their contactwith the compressed fluid anti-solvent.
 18. The method of claim 17,wherein the two or more fluids each carry one or more substances thatare to be combined in the particle formation vessel.
 19. The method ofclaim 2, wherein: the compressed fluid anti-solvent, having a kineticenergy, disperses the substance in the fluid vehicle by transferring thekinetic energy from the compressed fluid anti-solvent to the fluidvehicle; and the kinetic energy of the compressed fluid anti-solventextracts the fluid vehicle from the substance.
 20. The method of claim2, wherein the compressed fluid anti-solvent and the substance in thefluid vehicle contact each other immediately downstream of the point ofcompressed fluid anti-solvent entry into the particle formation vessel.21. The method of claim 20, wherein the contact between the compressedfluid anti-solvent and the substance in the fluid vehicle occurs betweenabout 0.5 seconds and about 10 seconds of the compressed fluidanti-solvent entering the particle formation vessel.
 22. The method ofclaim 21, wherein: the second fluid inlet has an outlet opening; and thecontact between the fluid anti-solvent and the substance in the fluidvehicle occurs at a distance from the compressed fluid anti-solvententering the particle formation vessel of between about 10 and about 40times a diameter of the outlet opening of the second fluid inlet. 23.The method of claim 21, wherein the contact between the fluidanti-solvent and the substance in the fluid vehicle occurs at a distancefrom the compressed fluid anti-solvent entering the particle formationvessel of between about 2 mm and about 8 mm.
 24. The method of claim 2,further comprising providing controlled agitation within the particleformation vessel in the region of fluid contact.
 25. The method of claim31, wherein the controlled agitation is selected from a list comprisingsonication and stirring.
 26. The method of claim 25, wherein thestirring is selected from a list of stirring methods comprising aturbine, a propeller, a paddle, and an impeller.
 27. The method of claim2, wherein the substance in the fluid vehicle is introduced directlyinto the flow of the compressed fluid anti-solvent.
 28. The method ofclaim 27, wherein the first fluid inlet terminates inside the flow ofthe compressed fluid anti-solvent coming out of the second fluid inlet.29. The method of claim 2, wherein the substance in the fluid vehicleand the compressed fluid anti-solvent meet, the angle between their axesof flow is between about 70° and about 110°.
 30. The method of claim 2,wherein the fluid vehicle comprises a fluid with a boiling point greaterthan about 150° C.
 31. The method of claim 30, wherein thepharmaceutical is salmeterol xinafoate,risperodone-(9-hydroxy)-palmitate, derivatives thereof, and combinationsthereof.
 32. The method of claim 6, wherein P₁, P₂, T₁ and T₂ areselected so as to form particles of the substance having a volume meandiameter of less than 5 μm.
 33. The method of claim 32, wherein P₁, P₂,T₁ and T₂ are selected so as to form particles of the substance having avolume mean diameter of less than 1 μm.
 34. The method of claim 6,wherein P₁, P₂, T₁ and T₂ are selected so as to form particles of thesubstance having a size distribution with a standard deviation of 2.5 orless.
 35. The method of claim 2, wherein the compressed fluidanti-solvent contains one or more modifiers.
 36. The method of claim 35,wherein the one or more modifiers are selected from the group of water,methanol, ethanol, isopropanol, and acetone.
 37. The method of claim 35,wherein the one or more modifiers constitutes between about 1 mole % andabout 40 mole % of the anti-solvent fluid.
 38. A method for preparing asubstance in particulate form, the method comprising: introducing into aparticle formation vessel the substance in a fluid vehicle through afirst fluid inlet, wherein the particle formation vessel has a pressureP₁ and a Temperature T₁; introducing into the particle formation vessela compressed fluid anti-solvent for the substance through a second fluidinlet, wherein the compressed fluid anti-solvent is introduced through arestricted inlet so as to have a back pressure of P₂ so that P₂ isgreater than P₁, wherein the compressed fluid anti-solvent has atemperature T₂ so that T₂ is greater than T₁, and wherein T₁ and T₂ aresuch that Joule-Thomson cooling of the compressed fluid anti-solvent asit enters the particle formation vessel does not reduce temperature ofthe compressed fluid anti-solvent to below that required of it toproduce particles; and allowing the compressed fluid anti-solvent toextract the fluid vehicle from the substance to form particles of thesubstance, wherein the compressed fluid anti-solvent has a sonic,near-sonic or supersonic velocity as it enters the particle formationvessel, wherein the compressed fluid anti-solvent and the substance inthe fluid vehicle enter the particle formation vessel at differentlocations and meet downstream in the particle formation vessel.
 39. Amethod for preparing a pharmaceutically active substance in particulateform, the method comprising: introducing into a particle formationvessel the pharmaceutically active substance in a fluid vehicle througha first fluid inlet; introducing into the particle formation vesselnear-critical or supercritical carbon dioxide through a second fluidinlet; and allowing the near-critical or supercritical carbon dioxide toextract the fluid vehicle from the pharmaceutically active substance toform particles of the pharmaceutically active substance, wherein thenear-critical or supercritical carbon dioxide has a sonic, near-sonic orsupersonic velocity as it enters the particle formation vessel, whereinthe near-critical or supercritical carbon dioxide and thepharmaceutically active substance in the fluid vehicle enter theparticle formation vessel at different locations and meet downstream inthe particle formation vessel.